Treating and preventing neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington’s disease have become significant challenges in the field of neurological research. In the early stages of neurodegenerative disease research, scientists often choose appropriate animal models to delve deeper into their molecular pathological mechanisms and macroscopic clinical manifestations. Selecting the right animal model is a crucial step in initiating and advancing this research process. This article focuses on analyzing various animal models used in the field of neurodegenerative diseases in recent years, with a particular focus on Huntington’s disease. It discusses in detail the advantages and disadvantages of different animal models in experimental research, as well as the pathological features and clinical manifestations they exhibit.
{"title":"Advantages and differences among various animal models of Huntington’s disease","authors":"Zhu Yu, Wenhao Yang, Sen Yan","doi":"10.20517/and.2024.13","DOIUrl":"https://doi.org/10.20517/and.2024.13","url":null,"abstract":"Treating and preventing neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington’s disease have become significant challenges in the field of neurological research. In the early stages of neurodegenerative disease research, scientists often choose appropriate animal models to delve deeper into their molecular pathological mechanisms and macroscopic clinical manifestations. Selecting the right animal model is a crucial step in initiating and advancing this research process. This article focuses on analyzing various animal models used in the field of neurodegenerative diseases in recent years, with a particular focus on Huntington’s disease. It discusses in detail the advantages and disadvantages of different animal models in experimental research, as well as the pathological features and clinical manifestations they exhibit.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"11 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141920504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glial cells populate the central nervous system and undertake indispensable roles in safeguarding and maintaining optimal neuronal performance. Throughout life, the brain undergoes inevitable changes that impact both neurons and glial cells. Concurrent with age-related neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), metabolic dysfunctions in glial cells are consistently observed. Though widely debated, the idea of treating neurodegenerative disorders by manipulating brain bioenergetics warrants further exploration. This review discusses the distinctive metabolic characteristics of central nervous system (CNS) glia, the metabolic deviations that occur in glial cells in the aging brain, and the ramifications of metabolic rewiring within glia on neurodegenerative disorders, specifically PD. We focus on astrocytes and microglia due to their substantial transformations under aging and diseased states, known as reactivation. Special attention is given to clarifying the complex relationships between dysregulated glial energy metabolism and brain disorders. By discussing both classic theories and current advances in this field, we aim to shed light on promising therapeutic horizons anchored in the strategic calibration of glial metabolic configurations.
{"title":"Age-related energetic reprogramming in glial cells: possible correlations with Parkinson’s disease","authors":"Boling Chu, Hongling Xiang, Han Wang, Yuting Lin, Rui Li, Jing Hu, Hao Qian","doi":"10.20517/and.2024.11","DOIUrl":"https://doi.org/10.20517/and.2024.11","url":null,"abstract":"Glial cells populate the central nervous system and undertake indispensable roles in safeguarding and maintaining optimal neuronal performance. Throughout life, the brain undergoes inevitable changes that impact both neurons and glial cells. Concurrent with age-related neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), metabolic dysfunctions in glial cells are consistently observed. Though widely debated, the idea of treating neurodegenerative disorders by manipulating brain bioenergetics warrants further exploration. This review discusses the distinctive metabolic characteristics of central nervous system (CNS) glia, the metabolic deviations that occur in glial cells in the aging brain, and the ramifications of metabolic rewiring within glia on neurodegenerative disorders, specifically PD. We focus on astrocytes and microglia due to their substantial transformations under aging and diseased states, known as reactivation. Special attention is given to clarifying the complex relationships between dysregulated glial energy metabolism and brain disorders. By discussing both classic theories and current advances in this field, we aim to shed light on promising therapeutic horizons anchored in the strategic calibration of glial metabolic configurations.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"189 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141828764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sheng-Rong Meng, Chao Ma, Jie Chen, Li-Qiang Wang, Hong-Yu Hu, Yi Liang
Aims: The misfolding of ataxin-3 in neurons is the hallmark of a neurodegenerative disease, spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). Ataxin-3 consists of a N-terminal Josephin domain and a C-terminal polyglutamine (polyQ) tract. The length of the polyQ tract is positively correlated with the disease. The aggregation of ataxin-3 in vitro is a two-step process, with the first step involving the aggregation of the Josephin domain and the second step involving an expanded polyQ tract. However, the fibril-forming motif of the Josephin domain is not well understood. Methods: In this study, we employed 3D profile algorithm and scanning proline mutagenesis to identify the fibril-forming motif of non-expanded ataxin-3. Results: By using thioflavin T fluorescence kinetics, sarkosyl-insoluble SDS-PAGE, transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR), we identified the fibril-forming motif of the Josephin domain of non-expanded ataxin-3 as 79VISNAL84. Conclusions: We demonstrated that the proline mutation in the fibril-forming motif of the Josephin domain could inhibit the aggregation of expanded ataxin-3, which shows some therapeutic promise.
目的：神经元中的共济失调蛋白-3（ataxin-3）的错误折叠是一种神经退行性疾病--脊髓小脑共济失调 3 型（SCA3）（又称马查多-约瑟夫病（MJD））的特征。Ataxin-3 由一个 N 端约瑟芬结构域和一个 C 端聚谷氨酰胺（polyQ）束组成。聚Q束的长度与疾病呈正相关。Ataxin-3 在体外的聚集过程分为两步，第一步涉及 Josephin 结构域的聚集，第二步涉及 polyQ 道的扩展。然而，Josephin 结构域的纤维形成基序尚不十分清楚。研究方法在这项研究中，我们采用了三维剖面算法和扫描脯氨酸诱变来确定非扩展的 ataxin-3 的纤维形成基调。结果通过使用硫黄素 T 荧光动力学、Sarkosyl-不溶性 SDS-PAGE、透射电子显微镜（TEM）和傅立叶变换红外光谱（FTIR），我们确定了非扩张型 ataxin-3 的 Josephin 结构域的纤维形成基序为 79VISNAL84。结论：我们证明了约瑟芬结构域纤维形成基团中的脯氨酸突变可抑制扩增的共济失调蛋白-3的聚集，具有一定的治疗前景。
{"title":"Fibril-forming motif of non-expanded ataxin-3 revealed by scanning proline mutagenesis","authors":"Sheng-Rong Meng, Chao Ma, Jie Chen, Li-Qiang Wang, Hong-Yu Hu, Yi Liang","doi":"10.20517/and.2023.15","DOIUrl":"https://doi.org/10.20517/and.2023.15","url":null,"abstract":"Aims: The misfolding of ataxin-3 in neurons is the hallmark of a neurodegenerative disease, spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). Ataxin-3 consists of a N-terminal Josephin domain and a C-terminal polyglutamine (polyQ) tract. The length of the polyQ tract is positively correlated with the disease. The aggregation of ataxin-3 in vitro is a two-step process, with the first step involving the aggregation of the Josephin domain and the second step involving an expanded polyQ tract. However, the fibril-forming motif of the Josephin domain is not well understood.\u0000 Methods: In this study, we employed 3D profile algorithm and scanning proline mutagenesis to identify the fibril-forming motif of non-expanded ataxin-3.\u0000 Results: By using thioflavin T fluorescence kinetics, sarkosyl-insoluble SDS-PAGE, transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR), we identified the fibril-forming motif of the Josephin domain of non-expanded ataxin-3 as 79VISNAL84.\u0000 Conclusions: We demonstrated that the proline mutation in the fibril-forming motif of the Josephin domain could inhibit the aggregation of expanded ataxin-3, which shows some therapeutic promise.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"50 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141358532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. Zhao, Yang Qiao, J. Yue, Ying Jing, Qiu Ge, Meng Zhang, Jianguo Zhang, Yuan Zhen, Yu-Tao Xiang, Jue Wang, Yuding Zang
Aim: Many resting-state functional magnetic resonance imaging (rs-fMRI) studies have provided evidence that repetitive transcranial magnetic stimulation (rTMS) exerts treatment effects via functional connectivity (FC) from a superficial stimulation target to a deep effective region. The dorsolateral subthalamic nucleus (DL-STN) is an effective target in deep brain stimulation surgery for Parkinson’s disease (PD), but its targeting highly depends on well-trained neurosurgeons and is not easily used for FC-guided rTMS. We aimed to devise a method for automatically localizing the DL-STN, and further develop a one-stop plug-in of rs-fMRI FC analysis to assist future individualized FC-guided rTMS. Methods: Based on structural and iron-sensitive MRI of 78 participants, two raters defined the DL-STN coordinates with very high reliability. The averaged coordinates in the standard Montreal Neurological Institute (MNI) space were: left DL-STN, x: -11.89 ± 0.82, y: -14.51 ± 1.00, and z: -6.40 ± 1.01 and the right DL-STN, x: 12.53 ± 0.77, y: -13.97 ± 0.86, and z: -6.57 ± 0.99. As the individual distances from the averaged coordinates were less than 3 mm (within one voxel for most rs-fMRI studies) for all 78 participants, we defined the average coordinates as AutoSTN. We then developed a one-stop plug-in named Connectivity and Coordinates Converting Assistant Toolbox (CC-CAT) and performed AutoSTN FC analysis. Results: The AutoSTN seed showed significant FC with the motor cortices in all participants. Conclusion: The AutoSTN-based rs-fMRI FC could guide future rTMS on PD. The one-stop plug-in CC-CAT can be used for any FC-guided rTMS treatment.
目的：许多静息态功能磁共振成像（rs-fMRI）研究证明，重复经颅磁刺激（rTMS）是通过从浅层刺激靶点到深层有效区域的功能连接（FC）发挥治疗效果的。在帕金森病（PD）的深部脑刺激手术中，背外侧丘脑下核（DL-STN）是一个有效靶点，但其靶点选择高度依赖于训练有素的神经外科医生，且不易用于 FC 引导的经颅磁刺激。我们的目的是设计一种自动定位 DL-STN 的方法，并进一步开发一种一站式 rs-fMRI FC 分析插件，以协助未来的个体化 FC 引导经颅磁刺激。研究方法根据78名参与者的结构和铁敏感核磁共振成像，由两名评分员确定DL-STN坐标，其可靠性非常高。标准蒙特利尔神经研究所（MNI）空间中的平均坐标为：左侧 DL-STN，x：-11.89 ± 0.82，y：-14.51 ± 1.00：-14.51±1.00，z：-6.40±1.01；右侧 DL-STN，x：12.53±0.77，y：-13.97±0.86：-13.97±0.86，z：-6.57±0.99。由于所有 78 名参与者与平均坐标的单个距离均小于 3 毫米（对于大多数 rs-fMRI 研究而言，均小于一个体素），因此我们将平均坐标定义为 AutoSTN。然后，我们开发了一个名为 "连接性和坐标转换助手工具箱（CC-CAT）"的一站式插件，并进行了 AutoSTN FC 分析。结果显示在所有参与者中，AutoSTN 种子与运动皮层均显示出明显的 FC。结论基于AutoSTN的rs-fMRI FC可以指导未来对帕金森病的经颅磁刺激。一站式插件 CC-CAT 可用于任何 FC 指导的经颅磁刺激治疗。
{"title":"Automatically targeting the dorsolateral subthalamic nucleus for functional connectivity-guided rTMS therapy","authors":"N. Zhao, Yang Qiao, J. Yue, Ying Jing, Qiu Ge, Meng Zhang, Jianguo Zhang, Yuan Zhen, Yu-Tao Xiang, Jue Wang, Yuding Zang","doi":"10.20517/and.2023.31","DOIUrl":"https://doi.org/10.20517/and.2023.31","url":null,"abstract":"Aim: Many resting-state functional magnetic resonance imaging (rs-fMRI) studies have provided evidence that repetitive transcranial magnetic stimulation (rTMS) exerts treatment effects via functional connectivity (FC) from a superficial stimulation target to a deep effective region. The dorsolateral subthalamic nucleus (DL-STN) is an effective target in deep brain stimulation surgery for Parkinson’s disease (PD), but its targeting highly depends on well-trained neurosurgeons and is not easily used for FC-guided rTMS. We aimed to devise a method for automatically localizing the DL-STN, and further develop a one-stop plug-in of rs-fMRI FC analysis to assist future individualized FC-guided rTMS.\u0000 Methods: Based on structural and iron-sensitive MRI of 78 participants, two raters defined the DL-STN coordinates with very high reliability. The averaged coordinates in the standard Montreal Neurological Institute (MNI) space were: left DL-STN, x: -11.89 ± 0.82, y: -14.51 ± 1.00, and z: -6.40 ± 1.01 and the right DL-STN, x: 12.53 ± 0.77, y: -13.97 ± 0.86, and z: -6.57 ± 0.99. As the individual distances from the averaged coordinates were less than 3 mm (within one voxel for most rs-fMRI studies) for all 78 participants, we defined the average coordinates as AutoSTN. We then developed a one-stop plug-in named Connectivity and Coordinates Converting Assistant Toolbox (CC-CAT) and performed AutoSTN FC analysis.\u0000 Results: The AutoSTN seed showed significant FC with the motor cortices in all participants.\u0000 Conclusion: The AutoSTN-based rs-fMRI FC could guide future rTMS on PD. The one-stop plug-in CC-CAT can be used for any FC-guided rTMS treatment.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"113 46","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140985561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Memory naturally declines as we age, but the rapid loss of memory can be distressing for people living with Alzheimer’s disease (AD). How memories are formed and retrieved in the brain is not fully understood; it is thought to require plasticity to the synapses connecting neurons in a network of engram cells. Plasticity may occur either through changes to the volume and location of molecules and organelles within the synapse, or gross structural changes of synapses. Memory naturally declines as we age, as do many of the mechanisms required for learning and memory, such as changes in concentrations of the cytoskeletal structural protein Microtubule-Associated Protein Tau, reduced brain glucose metabolism, and sensitivities to insulin. The biggest risk factor for developing AD is ageing, yet only few studies try to reconcile the natural decline in functions we see with ageing with the dramatic impairment of these pathways in AD, such as Tau protein and energy homeostasis by neurons. This review will therefore explain the changes to metabolism, Tau protein, and memory impairment during ageing, and explore the latest research that links these processes to neurodegeneration seen in AD, and other Tauopathies. Understanding how ageing and dementia diverge may offer an important and underutilised avenue for therapeutic interventions to target metabolism in both “healthy” ageing and disease.
随着年龄的增长，记忆力会自然衰退，但对于阿尔茨海默氏症（AD）患者来说，记忆力的迅速衰退可能会让他们感到痛苦。记忆是如何在大脑中形成和检索的，目前尚不完全清楚；据认为，这需要连接刻画细胞网络中神经元的突触具有可塑性。可塑性可能通过改变突触内分子和细胞器的体积和位置，或通过突触结构的明显改变而发生。随着年龄的增长，记忆力会自然减退，学习和记忆所需的许多机制也是如此，如细胞骨架结构蛋白微管相关蛋白 Tau 浓度的变化、脑葡萄糖代谢的降低以及对胰岛素的敏感性。老年痴呆症发病的最大风险因素是老龄化，然而只有极少数研究试图将老龄化导致的功能自然衰退与老年痴呆症中这些通路（如 Tau 蛋白和神经元的能量平衡）的显著损伤相协调。因此，本综述将解释衰老过程中新陈代谢、Tau 蛋白和记忆损伤的变化，并探讨将这些过程与老年痴呆症和其他 Tau 病的神经变性联系起来的最新研究。了解老龄化和痴呆症是如何分化的，可为针对 "健康 "老龄化和疾病中的新陈代谢进行治疗干预提供一个重要而又未被充分利用的途径。
{"title":"Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia","authors":"Miranda Robbins","doi":"10.20517/and.2023.57","DOIUrl":"https://doi.org/10.20517/and.2023.57","url":null,"abstract":"Memory naturally declines as we age, but the rapid loss of memory can be distressing for people living with Alzheimer’s disease (AD). How memories are formed and retrieved in the brain is not fully understood; it is thought to require plasticity to the synapses connecting neurons in a network of engram cells. Plasticity may occur either through changes to the volume and location of molecules and organelles within the synapse, or gross structural changes of synapses. Memory naturally declines as we age, as do many of the mechanisms required for learning and memory, such as changes in concentrations of the cytoskeletal structural protein Microtubule-Associated Protein Tau, reduced brain glucose metabolism, and sensitivities to insulin. The biggest risk factor for developing AD is ageing, yet only few studies try to reconcile the natural decline in functions we see with ageing with the dramatic impairment of these pathways in AD, such as Tau protein and energy homeostasis by neurons. This review will therefore explain the changes to metabolism, Tau protein, and memory impairment during ageing, and explore the latest research that links these processes to neurodegeneration seen in AD, and other Tauopathies. Understanding how ageing and dementia diverge may offer an important and underutilised avenue for therapeutic interventions to target metabolism in both “healthy” ageing and disease.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"44 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aging is the biggest risk factor for Parkinson’s disease (PD) and a particular vulnerability of dopaminergic neurons in the substantia nigra to aging-associated effects has been firmly established. More recent work has revealed an important role of non-neuronal systems such as the blood-brain barrier (BBB) or the immune system in the pathogenesis of PD. Effects of aging on the immune system include a chronic inflammatory state termed inflammaging and immunosenescence. Both processes are connected to a higher pro-inflammatory potency and negatively affect the maintenance of self-tolerance. The BBB gets increasingly dysfunctional with advancing age and its endothelial cells display a more pro-inflammatory phenotype while the transport of important plasma proteins to the brain is impaired. The immune system and the BBB are heavily interdependent and are both essential for the homeostasis of especially vulnerable dopaminergic neurons. The degeneration of dopaminergic neurons can, in turn, influence the BBB or the immune system, potentially creating a vicious cycle. In this review, we aim to develop a multisystem perspective on aging and PD by incorporating the aging immune system and aging BBB into the pathophysiological processes. Given the current evidence, it seems likely that a combination of multimodal effects of aging on the levels of SN pars compacta (SNc) dopaminergic neurons, the immune system, and the BBB increase the risk of developing PD.
衰老是帕金森病（PD）的最大风险因素，而黑质中的多巴胺能神经元特别容易受到衰老相关效应的影响，这一点已得到证实。最近的研究发现，血脑屏障（BBB）或免疫系统等非神经元系统在帕金森病的发病机制中发挥着重要作用。衰老对免疫系统的影响包括慢性炎症状态，即炎症老化和免疫衰老。这两个过程都与较高的促炎效力有关，并对自我耐受的维持产生负面影响。随着年龄的增长，BBB 的功能日益失调，其内皮细胞显示出更多的促炎表型，同时向大脑运输重要血浆蛋白的功能也受到损害。免疫系统和 BBB 在很大程度上相互依存，对于特别脆弱的多巴胺能神经元的平衡至关重要。多巴胺能神经元的退化反过来又会影响 BBB 或免疫系统，从而可能造成恶性循环。在这篇综述中，我们将老化的免疫系统和老化的 BBB 纳入病理生理过程，旨在从多系统的角度探讨衰老和帕金森病。鉴于目前的证据，衰老对SN pars compacta（SNc）多巴胺能神经元水平、免疫系统和BBB的多模式效应似乎有可能增加罹患帕金森病的风险。
{"title":"Aging and Parkinson’s disease: a complex interplay of vulnerable neurons, the immune system and the blood-brain barrier","authors":"J. Bendig, Anika Frank, Heinz Reichmann","doi":"10.20517/and.2023.36","DOIUrl":"https://doi.org/10.20517/and.2023.36","url":null,"abstract":"Aging is the biggest risk factor for Parkinson’s disease (PD) and a particular vulnerability of dopaminergic neurons in the substantia nigra to aging-associated effects has been firmly established. More recent work has revealed an important role of non-neuronal systems such as the blood-brain barrier (BBB) or the immune system in the pathogenesis of PD. Effects of aging on the immune system include a chronic inflammatory state termed inflammaging and immunosenescence. Both processes are connected to a higher pro-inflammatory potency and negatively affect the maintenance of self-tolerance. The BBB gets increasingly dysfunctional with advancing age and its endothelial cells display a more pro-inflammatory phenotype while the transport of important plasma proteins to the brain is impaired. The immune system and the BBB are heavily interdependent and are both essential for the homeostasis of especially vulnerable dopaminergic neurons. The degeneration of dopaminergic neurons can, in turn, influence the BBB or the immune system, potentially creating a vicious cycle. In this review, we aim to develop a multisystem perspective on aging and PD by incorporating the aging immune system and aging BBB into the pathophysiological processes. Given the current evidence, it seems likely that a combination of multimodal effects of aging on the levels of SN pars compacta (SNc) dopaminergic neurons, the immune system, and the BBB increase the risk of developing PD.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"2 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140375263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Suman Rimal, Wen Li, Tejender Pal Khaket, Yu Li, Ishaq Tantray, Yanping Li, Sunil Bhurtel, L. Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu
Aim: Oxidative stress and NAD+/NADH imbalance caused by alterations in reactive oxygen species (ROS) and NAD(H) metabolism are pathological features associated with normal aging and age-related diseases including Alzheimer’s disease (AD). How abnormalities in ROS and NAD(H) metabolism occur under these pathological conditions is not well understood, nor is it known whether they are mechanistically linked and can be therapeutically targeted together. The aim of this study is to identify the cause of aberrant ROS and NAD(H) metabolism and test its role in the pathogenesis of AD. Methods: Reverse electron transport (RET) along mitochondrial complex I can occur under certain thermodynamic conditions, leading to excessive ROS generation and NAD+ conversion to NADH, and thus lowered NAD+/NADH ratio. Brain samples from AD patients and mouse AD models were used to assess the status of RET by measuring ROS and NAD+/NADH ratio in brain lysates and purified mitochondria respiring under RET conditions. A small molecule RET inhibitor was used to treat APP(swe)/PS1(deltaE9) and 5xFAD mouse models and human induced pluripotent stem cell (iPSC)-derived neuronal model of AD. Effects on behavior and AD-related neuropathology were examined. The biochemical mechanism underlying RET alteration was examined by protein-protein interaction studies. Results: RET is aberrantly activated in transgenic AD mouse brains and in individuals with AD. Pharmacological inhibition of RET reduced amyloid burden and neuroinflammation and rescued cognitive and behavioral deficits in the APP(swe)/PS1(deltaE9) and 5xFAD mouse models. In human AD iPSC-derived neurons, RET inhibition reduced amyloid aggregation, tau hyperphosphorylation, and early endosomal defects. Mechanistically, the AD-associated amyloid precursor protein C-terminal fragment (APP.C99) was found to interact with complex I proteins to promote RET. Conclusion: RET is aberrantly activated in AD, causing altered ROS and NAD+/NADH metabolism. Pharmacological inhibition of RET is beneficial in mouse and human iPSC models of AD. RET activation represents a key pathological driver and a rational therapeutic target for AD and possibly other age-related neurodegenerative diseases.
目的：活性氧（ROS）和 NAD（H）代谢改变导致的氧化应激和 NAD+/NADH 失衡是与正常衰老和包括阿尔茨海默病（AD）在内的老年相关疾病相关的病理特征。目前还不太清楚在这些病理条件下如何发生活性氧和 NAD(H) 代谢异常，也不知道它们之间是否存在机理联系并可同时作为治疗靶点。本研究旨在确定 ROS 和 NAD(H) 代谢异常的原因，并检验其在 AD 发病机制中的作用。研究方法在某些热力学条件下，线粒体复合物 I 会发生逆电子传递（RET），导致产生过多的 ROS 和 NAD+ 转化为 NADH，从而降低 NAD+/NADH 比率。通过测量在 RET 条件下呼吸的脑裂解物和纯化线粒体中的 ROS 和 NAD+/NADH 比率，我们利用 AD 患者和小鼠 AD 模型的脑样本来评估 RET 的状态。一种小分子 RET 抑制剂被用于治疗 APP(swe)/PS1(deltaE9) 和 5xFAD 小鼠模型以及人类诱导多能干细胞（iPSC）衍生的 AD 神经元模型。研究还考察了RET对行为和AD相关神经病理学的影响。蛋白质相互作用研究探讨了 RET 改变的生化机制。研究结果在转基因 AD 小鼠大脑和 AD 患者中，RET 被异常激活。药理抑制 RET 可减轻淀粉样蛋白负荷和神经炎症，并能挽救 APP(swe)/PS1(deltaE9) 和 5xFAD 小鼠模型的认知和行为缺陷。在人类 AD iPSC 衍生神经元中，抑制 RET 可减少淀粉样蛋白聚集、tau 过度磷酸化和早期内体缺陷。从机理上讲，AD相关淀粉样前体蛋白C端片段（APP.C99）与复合体I蛋白相互作用，促进了RET。结论RET在AD中异常激活，导致ROS和NAD+/NADH代谢改变。药理抑制 RET 对小鼠和人类 iPSC 多发性硬化症模型有益。RET 激活是一种关键的病理驱动因素，也是 AD 以及其他可能与年龄相关的神经退行性疾病的合理治疗靶点。
{"title":"Deregulation of mitochondrial reverse electron transport alters the metabolism of reactive oxygen species and NAD+/NADH and presents a therapeutic target in Alzheimer’s disease","authors":"Suman Rimal, Wen Li, Tejender Pal Khaket, Yu Li, Ishaq Tantray, Yanping Li, Sunil Bhurtel, L. Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu","doi":"10.20517/and.2024.07","DOIUrl":"https://doi.org/10.20517/and.2024.07","url":null,"abstract":"Aim: Oxidative stress and NAD+/NADH imbalance caused by alterations in reactive oxygen species (ROS) and NAD(H) metabolism are pathological features associated with normal aging and age-related diseases including Alzheimer’s disease (AD). How abnormalities in ROS and NAD(H) metabolism occur under these pathological conditions is not well understood, nor is it known whether they are mechanistically linked and can be therapeutically targeted together. The aim of this study is to identify the cause of aberrant ROS and NAD(H) metabolism and test its role in the pathogenesis of AD.\u0000 Methods: Reverse electron transport (RET) along mitochondrial complex I can occur under certain thermodynamic conditions, leading to excessive ROS generation and NAD+ conversion to NADH, and thus lowered NAD+/NADH ratio. Brain samples from AD patients and mouse AD models were used to assess the status of RET by measuring ROS and NAD+/NADH ratio in brain lysates and purified mitochondria respiring under RET conditions. A small molecule RET inhibitor was used to treat APP(swe)/PS1(deltaE9) and 5xFAD mouse models and human induced pluripotent stem cell (iPSC)-derived neuronal model of AD. Effects on behavior and AD-related neuropathology were examined. The biochemical mechanism underlying RET alteration was examined by protein-protein interaction studies.\u0000 Results: RET is aberrantly activated in transgenic AD mouse brains and in individuals with AD. Pharmacological inhibition of RET reduced amyloid burden and neuroinflammation and rescued cognitive and behavioral deficits in the APP(swe)/PS1(deltaE9) and 5xFAD mouse models. In human AD iPSC-derived neurons, RET inhibition reduced amyloid aggregation, tau hyperphosphorylation, and early endosomal defects. Mechanistically, the AD-associated amyloid precursor protein C-terminal fragment (APP.C99) was found to interact with complex I proteins to promote RET.\u0000 Conclusion: RET is aberrantly activated in AD, causing altered ROS and NAD+/NADH metabolism. Pharmacological inhibition of RET is beneficial in mouse and human iPSC models of AD. RET activation represents a key pathological driver and a rational therapeutic target for AD and possibly other age-related neurodegenerative diseases.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":" 44","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140212601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder due to a triplet repeat expansion in the HTT gene. The identification of this gene variation was a lengthy process, but it has since provided an explanation of clinical observations including the variability in age at onset observed across generations (phenomenon of anticipation). Further molecular genetic investigations have allowed the discovery of genes modifying the phenotype presenting differences in terms of age at the onset and course of the disease. Pathogenic gene variations have also been found in other diseases with a similar presentation, such as HD, allowing precise genetic diagnosis. This narrative review examines these data in the context of their historical development. Their implication in our understanding of these disorders and treatment modalities is also highlighted.
{"title":"Genetics of Huntington’s disease and related disorders: beyond triplet repeats","authors":"J. Burgunder","doi":"10.20517/and.2023.49","DOIUrl":"https://doi.org/10.20517/and.2023.49","url":null,"abstract":"Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder due to a triplet repeat expansion in the HTT gene. The identification of this gene variation was a lengthy process, but it has since provided an explanation of clinical observations including the variability in age at onset observed across generations (phenomenon of anticipation). Further molecular genetic investigations have allowed the discovery of genes modifying the phenotype presenting differences in terms of age at the onset and course of the disease. Pathogenic gene variations have also been found in other diseases with a similar presentation, such as HD, allowing precise genetic diagnosis. This narrative review examines these data in the context of their historical development. Their implication in our understanding of these disorders and treatment modalities is also highlighted.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140412771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elisabeth C. DeMarco, Jason Longhurst, Leslie Hinyard
Parkinson’s disease (PD) is a neurodegenerative disease comprised of motor and non-motor symptoms, including depression and anxiety. The relationship between depression, anxiety, and motor symptoms is not well understood. Additionally, there are few direct comparisons of anxiety and depression between people with PD (PwP) and those without PD. The present study determined differences in state and trait anxiety between those with and without PD, examined the impact of depression on anxiety in both groups, and explored the relationship between depression, anxiety, and motor symptoms among PwP. Data from 42 PwP and 56 non-PD comparison participants were obtained from a non-randomized, non-treatment longitudinal observational study. Anxiety [State-Trait Anxiety Inventory (STAI)], depression (Geriatric Depression Screen), and motor symptoms (Movement Disorder Society - Unified Parkinson’s Disease Rating Scale part III) were assessed. There were no statistically significant differences between PwP and non-PD comparisons for anxiety or depression. Depression was associated with elevated STAI scores (P < 0.001) regardless of PD status. Depressed PwP displayed greater motor symptom burden compared to non-depressed PwP (median [IQR]: 25.00 [21.00, 38.50] vs. 20.00 [16.00, 23.00]; P = 0.064). There were statistically significant differences in both state and trait anxiety when participants were grouped by depression and PD status. While anxiety does not appear to be correlated with motor symptoms in people with PD, depression may be associated with greater motor symptom burden. Further study is needed to explore the relationship between depression, anxiety, and motor impairment in PwP.
帕金森病（PD）是一种由运动症状和非运动症状（包括抑郁和焦虑）组成的神经退行性疾病。抑郁、焦虑和运动症状之间的关系尚不十分清楚。此外，对帕金森氏症患者（PwP）和非帕金森氏症患者的焦虑和抑郁进行直接比较的情况也很少。本研究确定了帕金森病患者和非帕金森病患者在状态焦虑和特质焦虑方面的差异，检查了抑郁症对两组患者焦虑的影响，并探讨了帕金森病患者抑郁、焦虑和运动症状之间的关系。42 名帕金森病患者和 56 名非帕金森病对比参与者的数据来自一项非随机、非治疗的纵向观察研究。研究评估了焦虑（状态-特质焦虑量表 (STAI)）、抑郁（老年抑郁筛查）和运动症状（运动障碍协会-统一帕金森病评分量表第三部分）。在焦虑或抑郁方面，帕金森病患者与非帕金森病患者之间没有明显的统计学差异。无论帕金森病状态如何，抑郁都与 STAI 评分升高有关（P < 0.001）。与非抑郁症患者相比，抑郁症患者的运动症状负担更大（中位数 [IQR]: 25.00 [21.00, 38.50] vs. 20.00 [16.00, 23.00]; P = 0.064）。根据抑郁和帕金森病状况对参与者进行分组后，他们的状态焦虑和特质焦虑在统计学上存在显著差异。虽然焦虑似乎与帕金森病患者的运动症状无关，但抑郁可能与更大的运动症状负担有关。我们需要进一步研究抑郁、焦虑和运动障碍之间的关系。
{"title":"Exploring relationships between state and trait anxiety and depression in patients with Parkinson’s disease and controls: a cross-sectional analysis","authors":"Elisabeth C. DeMarco, Jason Longhurst, Leslie Hinyard","doi":"10.20517/and.2023.33","DOIUrl":"https://doi.org/10.20517/and.2023.33","url":null,"abstract":"Parkinson’s disease (PD) is a neurodegenerative disease comprised of motor and non-motor symptoms, including depression and anxiety. The relationship between depression, anxiety, and motor symptoms is not well understood. Additionally, there are few direct comparisons of anxiety and depression between people with PD (PwP) and those without PD. The present study determined differences in state and trait anxiety between those with and without PD, examined the impact of depression on anxiety in both groups, and explored the relationship between depression, anxiety, and motor symptoms among PwP. Data from 42 PwP and 56 non-PD comparison participants were obtained from a non-randomized, non-treatment longitudinal observational study. Anxiety [State-Trait Anxiety Inventory (STAI)], depression (Geriatric Depression Screen), and motor symptoms (Movement Disorder Society - Unified Parkinson’s Disease Rating Scale part III) were assessed. There were no statistically significant differences between PwP and non-PD comparisons for anxiety or depression. Depression was associated with elevated STAI scores (P < 0.001) regardless of PD status. Depressed PwP displayed greater motor symptom burden compared to non-depressed PwP (median [IQR]: 25.00 [21.00, 38.50] vs. 20.00 [16.00, 23.00]; P = 0.064). There were statistically significant differences in both state and trait anxiety when participants were grouped by depression and PD status. While anxiety does not appear to be correlated with motor symptoms in people with PD, depression may be associated with greater motor symptom burden. Further study is needed to explore the relationship between depression, anxiety, and motor impairment in PwP.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"54 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140482577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Telomeres, essential DNA-protein complexes located at chromosome ends, play a critical role in preventing chromosome fusion, recombination, and degradation, thus ensuring genomic stability. When telomeres reach a limiting shortened length, they will activate DNA damage checkpoints, stop cell division and trigger replicative senescence. Telomerase is composed of RNA and protein, which can synthesize telomeres repeat sequences, and elongate telomeres. Studies have shown that telomere length (TL) and telomerase activity are closely involved in aging, aging-related degenerative diseases, and tumors. Neurodegenerative diseases (NDDs) are one of the major aging-related diseases caused by both genetic and environmental factors, characterized by insidious onset, difficult diagnosis, irreversible disease progression, and lack of effective treatments, which brings a heavy burden to society and families. Currently, many studies have noted variations in leukocyte telomere length (LTL) and telomerase activity in NDDs, suggesting a vital role for telomeres and telomerase in NDD pathogenesis. This review explores the relationship between TL and NDDs, examines telomerase as a potential therapeutic target, and discusses emerging biomarkers and intervention strategies for NDD diagnosis and treatment.
端粒是位于染色体末端的重要 DNA 蛋白复合物，在防止染色体融合、重组和降解方面发挥着关键作用，从而确保基因组的稳定性。当端粒达到极限缩短长度时，就会激活DNA损伤检查点，停止细胞分裂，引发复制衰老。端粒酶由核糖核酸（RNA）和蛋白质组成，可以合成端粒重复序列，延长端粒。研究表明，端粒长度（TL）和端粒酶活性与衰老、与衰老相关的退行性疾病和肿瘤密切相关。神经退行性疾病（NDDs）是由遗传和环境因素引起的主要衰老相关疾病之一，具有起病隐匿、诊断困难、疾病进展不可逆、缺乏有效治疗等特点，给社会和家庭带来沉重负担。目前，许多研究都注意到了NDD中白细胞端粒长度（LTL）和端粒酶活性的变化，这表明端粒和端粒酶在NDD发病机制中起着至关重要的作用。本综述探讨了端粒长度与 NDD 之间的关系，研究了作为潜在治疗靶点的端粒酶，并讨论了用于 NDD 诊断和治疗的新兴生物标记物和干预策略。
{"title":"Potential roles of telomeres and telomerase in neurodegenerative diseases","authors":"Jun Shao, Jing Wang, Bo Li, Chuanbin Liu","doi":"10.20517/and.2023.41","DOIUrl":"https://doi.org/10.20517/and.2023.41","url":null,"abstract":"Telomeres, essential DNA-protein complexes located at chromosome ends, play a critical role in preventing chromosome fusion, recombination, and degradation, thus ensuring genomic stability. When telomeres reach a limiting shortened length, they will activate DNA damage checkpoints, stop cell division and trigger replicative senescence. Telomerase is composed of RNA and protein, which can synthesize telomeres repeat sequences, and elongate telomeres. Studies have shown that telomere length (TL) and telomerase activity are closely involved in aging, aging-related degenerative diseases, and tumors. Neurodegenerative diseases (NDDs) are one of the major aging-related diseases caused by both genetic and environmental factors, characterized by insidious onset, difficult diagnosis, irreversible disease progression, and lack of effective treatments, which brings a heavy burden to society and families. Currently, many studies have noted variations in leukocyte telomere length (LTL) and telomerase activity in NDDs, suggesting a vital role for telomeres and telomerase in NDD pathogenesis. This review explores the relationship between TL and NDDs, examines telomerase as a potential therapeutic target, and discusses emerging biomarkers and intervention strategies for NDD diagnosis and treatment.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"2 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139525052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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